Polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE~ OMIM# 611087) is a severe developmental disorder characterized by intractable epilepsy, craniofacial dysmorphism, cognitive impairment, autism, and a high childhood mortality rate identified in the Old Order Mennonite community of Lancaster, PA. PMSE results from mutations in the STRADA gene. The encoded protein STRADA is believed to signal via LKB1:STRADA:MO25 complex through AMPK and mTOR to modulate cerebral cortical development. We have recently generated IPSC derived neurons from PMSE patients as a cell platform that can be screened with new pharmacological agents to rescue aberrant neuronal firing, hyperactivated mTOR pathway signaling, and abnormal cell morphology and motility. These experiments provide a human cell line derived from a neurodevelopmental disorder with a 100% association with epilepsy that can be directly tested to discover how neurons become epileptic over time and how new mTOR and AMPK signaling modulators can be targeted to prevent seizures. In the first Aim, we will assay how changes in cell size, morphology, an motility in PMSE neurons can be rescued with mTOR and AMPK pathway agonists and antagonists. In the second Aim, we will use patch clamp physiology approaches to show how aberrant cell firing can be rescued with mTOR and AMPK agonists and antagonists.